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Bronchial brushings' microRNA and field cancerization in lung adenocarcinoma [Meeting Abstract]
Tsay, J J; Tchou-Wong, K; Yie, T; Leibert, E; Segal, L N; Greenberg, A; Pass, H; Rom, W N
Rationale: Cigarette smoke causes a field of injury and molecular changes in the airways even in histologically normal areas termed "field cancerization" which describes the site(s) of neoplasia and adjacent normal tissue with molecular abnormalities in common. MicroRNAs ( miRNAs) are small, non-coding RNAs that act as post-transcriptional regulators of gene expression by recognizing target sites in the 3' untranslated regions (3'UTRs) via incomplete base-pairing and induce mRNA degradation or translational repression. Deregulation of miRNAs has been linked to cancer initiation and progression, and miRNAs may act as tumor suppressor genes or oncogenes. We hypothesized that miRNA expression in the peripheral airways of smokers with lung cancer is distinct from that of smokers without lung cancer and therefore, miRNAs can be used as biomarkers for the early detection of lung cancer. Methods: We collected human peripheral airway epithelial cells by bronchoscopic brushing from the unaffected lung of thirteen smokers with lung adenocarcinoma and twelve control smokers. Total RNA was extracted from the peripheral airway epithelial cells by miRNAeasy and miRNA profiling was performed using the TaqMan Quantitative qRT-PCR miRNA Assay. Results: Comparison of miRNA levels in peripheral airway epithelial cells from smokers with or without lung cancer demonstrated 53 miRNAs that were significantly different (p<0.05) between the two groups. The majority of miRNAs were up-regulated (41 miRNAs) in lung cancer patients, including miR-21, miR-26a, miR-31, miR-34c, and miR-205. Down-regulated miRNAs included let-7b, let-7e, and miR-126. Several of the miRNAs with increased expression are of interest: miR-21 inhibits tumor suppressor protein PTEN, miR-26a suppresses PTEN and increases AKT phosphorylation and nuclear factor kappaB (NFkappaB) activation, miR-31 represses tumor suppressor genes LATS2 and PPP2R2A, miR-205 is associated with cancer relapses, and miR-34c, a p53 target induced by DNA damage, suggests the involvement of p53 pathway in field carcinogenesis. Down-regulated let-7b leads to higher expression of CYP2J2 and decreased miR-126 enhances adhesion, migration and invasion through increased Crk protein. Further gene expression and pathway analyses will corroborate the relationship between miRNAs and predicted pathways in real time. Conclusion: We discovered a profile of miRNAs in the contralateral lung of patients with lung cancer as biomarkers of field cancerization in smokers with lung adenocarcinoma. Further knowledge of field cancerization may lead to better understanding of tumorigenesis and development of biomarkers for early lung cancer detection
EMBASE:71984243
ISSN: 1073-449x
CID: 1769082
National Mesothelioma Virtual Bank: A Platform for Collaborative Research and Mesothelioma Biobanking Resource to Support Translational Research
Amin, Waqas; Parwani, Anil V; Melamed, Jonathan; Flores, Raja; Pennathur, Arjun; Valdivieso, Federico; Whelan, Nancy B; Landreneau, Rodeny; Luketich, James; Feldman, Michael; Pass, Harvey I; Becich, Michael J
The National Mesothelioma Virtual Bank (NMVB), developed six years ago, gathers clinically annotated human mesothelioma specimens for basic and clinical science research. During this period, this resource has greatly increased its collection of specimens by expanding the number of contributing academic health centers including New York University, University of Pennsylvania, University of Pittsburgh Medical Center, and Mount Sinai School of Medicine. Marketing efforts at both national and international annual conferences increase awareness and availability of the mesothelioma specimens at no cost to approved investigators, who query the web-based NMVB database for cumulative and appropriate patient clinicopathological information on the specimens. The data disclosure and specimen distribution protocols are tightly regulated to maintain compliance with participating institutions' IRB and regulatory committee reviews. The NMVB currently has over 1120 annotated cases available for researchers, including paraffin embedded tissues, fresh frozen tissue, tissue microarrays (TMA), blood samples, and genomic DNA. In addition, the resource offers expertise and assistance for collaborative research. Furthermore, in the last six years, the resource has provided hundreds of specimens to the research community. The investigators can request specimens and/or data by submitting a Letter of Intent (LOI) that is evaluated by NMVB research evaluation panel (REP).
PMCID:4437393
PMID: 26316942
ISSN: 2090-3197
CID: 1762532
Development of a multi-variate plasma proteomic classifier for the molecular characterization of pulmonary nodules [Meeting Abstract]
Vachani, A; Pass, H; Li, X; Lam, S; Chelsky, D; Hood, L; Kearney, P; Fang, K; Massion, P P; Rom, W N
RATIONALE. Diagnostic decision-making for patients with pulmonary nodules balances an individual's risk for non-small cell lung cancer (NSCLC) and the likelihood of benign disease. Management guidelines include serial CT observation or diagnostic resection, respectively, and PET scans and/or invasive biopsy procedures for 8-20 mm nodules, many of which are non-malignant. Recent lung cancer biomarker research suggests the potential utility of molecular adjuncts to augment clinicians' assessment of malignancy risk based on age, smoking history and nodule size. We explored the hypothesis that a multivariate protein panel may discriminate patients with malignant and benign nodules, and used selected reaction monitoring mass spectrometry (SRM-MS) to derive a 13-protein plasma classifier optimized for identifying benign nodules. METHODS. A systems biology approach was used to nominate 388 candidate proteins for classifier development. Using a retrospective, multi-center (n=4), and paired case-control study design, K2-EDTA plasma samples from lung nodule patients with pathologic diagnoses of NSCLC or benign disease were analyzed in independent discovery (D) (n=143) and validation (V) (n=104) sets. Cancer and benign samples were matched pairwise for age, gender and nodule size. Subject and nodule characteristics for cases/controls, respectively, included: age (mean), D:65/64, V:63/62; %male, D:40%/47%, V:48%/52%; smoking pack-years (mean), D:37/20, V:40/27; and nodule size (mm, mean), D:13/13, V:16/15. 70 microliter plasma aliquots immuno-depleted of high abundance proteins were analyzed by SRM-MS using the AB Sciex QTRAP 5500 LC/MS/MS system. RESULTS. Bioinformatic methods using Monte Carlo cross-validation, identification of best performing group proteins, and logistic regression analysis yielded 13 classifier and 6 normalization proteins. To optimize sensitivity for identifying benign nodules, the method of partial receiver operating characteristics area under the curve was utilized; the classifier demonstrated 93% sensitivity and 45% specificity in discovery, and using an estimated cancer prevalence of 20%, resulted in PPV and NPV of 30% and 96%, respectively. Similarly, in validation, it yielded 90% sensitivity and 27% specificity, with PPV and NPV of 24% and 90%, respectively. There was no correlation between classifier scores and age, smoking history pack-years or nodule size. Ingenuity Pathway Analysis mapped the 13 classifier proteins to 4 nuclear proteins (AHR, FOS, MYC, NRF2) regulating lung cancer, lung inflammation and oxidative stress responses. CONCLUSIONS. The use of a systems-based, proteomic strategy yielded a 13-protein plasma classifier prioritizing a high NPV with the potential for use as a non-invasive molecular adjunct for the early diagnosis of patients with pulmonary nodules
EMBASE:71985494
ISSN: 1073-449x
CID: 1768962
Clustering of lung adenocarcinomas classes using automated texture analysis on CT images
Pires, A.; Rusinek, H.; Suh, J.; Naidich, D.P.; Pass, H.; Ko, J.P.
Purpose: To assess whether automated texture analysis of CT images enables discrimination among pathologic classes of lung adenocarcinomas, and thus serves as an in vivo biomarker of lung cancer prognosis. Materials and Methods: Chest CTs of 30 nodules in 30 patients with resected adenocarcinomas were evaluated by a pulmonary pathologist who classified each resected cancer according to the International Association for the Study of Lung Cancer (IASLC) system. The categories included adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), lepidic-predominant adenocarcinoma (LPA), and other invasive adenocarcinomas (INV). 3D volumes of interest (VOIs) and 2D regions of interest (ROIs) were then constructed for each nodule. A comprehensive set of N=279 texture parameters were computed for both 3D and 2D regions. Clustering and classification of these parameters were performed with linear discriminant analysis (LDA) using features determined by optimal subsets. Results: Of the 30 adenocarcinomas, there were 13 INV, 11 LPA, 3 MIA, and 3 AIS. AIS and MIA groups were analyzed together. With all 3 classes, LDA classified 17 of 30 nodules correctly using the nearest neighbor (k=1) method. When only the two largest classes (INV and LPA) were used, 21 of 24 nodules were classified correctly. With 3 classes and 2D texture analysis, and when using only the two largest groups, LDA was able to correctly classify all nodules. Conclusion: CT texture parameters determined by optimal subsets allows for effective clustering of adenocarcinoma classes. These results suggest the potential use of automated (or computer-assisted) CT image analysis to predict the invasive pathologic character of lung nodules. Our approach overcomes the limitations of current radiologic interpretation, such as subjectivity, interand intra-observer variability, and the effect of reader experience
INSPEC:13750846
ISSN: 0277-786x
CID: 563752
Management of the Apical Tumor: May 4, 2013, Minneapolis, MN
Donington, Jessica; Vailleres, Eric; Bains, Manjit; Swisher, Stephen; Pass, Harvey
PMID: 24331149
ISSN: 1043-0679
CID: 753092
Development of a biosensor for detection of pleural mesothelioma cancer biomarker using surface imprinting
Mathur, Aabhas; Blais, Steven; Goparaju, Chandra M V; Neubert, Thomas; Pass, Harvey; Levon, Kalle
Hyaluronan-linked protein 1 (HAPLN1) which has been shown to be highly expressed in malignant pleural mesotheliomas (MPM), was detected in serum using an electrochemical surface-imprinting method. First, the detection method was optimized using Bovine serum albumin (BSA) as a model protein to mimic the optimal conditions required to imprint the similar molecular weight protein HAPLN1. BSA was imprinted on the gold electrode with hydroxyl terminated alkane thiols, which formed a self-assembled monolayer (SAM) around BSA. The analyte (BSA) was then washed away and its imprint (empty cavity with shape-memory) was used for detection of BSA in a solution, using electrochemical open-circuit potential method, namely potentiometry. Factors considered to optimize the conditions include incubation time, protein concentration, limit of detection and size of electrode. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was used to confirm selectivity of imprints. With the obtained imprinting control parameters, HAPLN1 was imprinted in duplicate and the detection of spiked HAPLN1 was successfully conducted in serum.
PMCID:3596364
PMID: 23516416
ISSN: 1932-6203
CID: 753322
Variant Ciz1 is a circulating biomarker for early-stage lung cancer
Higgins, Gillian; Roper, Katherine M; Watson, Irene J; Blackhall, Fiona H; Rom, William N; Pass, Harvey I; Ainscough, Justin F X; Coverley, Dawn
There is an unmet need for circulating biomarkers that can detect early-stage lung cancer. Here we show that a variant form of the nuclear matrix-associated DNA replication factor Ciz1 is present in 34/35 lung tumors but not in adjacent tissue, giving rise to stable protein quantifiable by Western blot in less than a microliter of plasma from lung cancer patients. In two independent sets, with 170 and 160 samples, respectively, variant Ciz1 correctly identified patients who had stage 1 lung cancer with clinically useful accuracy. For set 1, mean variant Ciz1 level in individuals without diagnosed tumors established a threshold that correctly classified 98% of small cell lung cancers (SCLC) and non-SCLC patients [receiver operator characteristic area under the curve (AUC) 0.958]. Within set 2, comparison of patients with stage 1 non-SCLC with asymptomatic age-matched smokers or individuals with benign lung nodules correctly classified 95% of patients (AUCs 0.913 and 0.905), with overall specificity of 76% and 71%, respectively. Moreover, using the mean of controls in set 1, we achieved 95% sensitivity among patients with stage 1 non-SCLC patients in set 2 with 74% specificity, demonstrating the robustness of the classification. RNAi-mediated selective depletion of variant Ciz1 is sufficient to restrain the growth of tumor cells that express it, identifying variant Ciz1 as a functionally relevant driver of cell proliferation in vitro and in vivo. The data show that variant Ciz1 is a strong candidate for a cancer-specific single marker capable of identifying early-stage lung cancer within at-risk groups without resort to invasive procedures.
PMCID:3494940
PMID: 23074256
ISSN: 0027-8424
CID: 183592
Biomarkers and prognostic factors for mesothelioma
Pass, Harvey I
PMCID:3741796
PMID: 23977535
ISSN: 2225-319x
CID: 512982
Initial Analysis of the International Association For the Study of Lung Cancer Mesothelioma Database
Rusch, Valerie W; Giroux, Dorothy; Kennedy, Catherine; Ruffini, Enrico; Cangir, Ayten K; Rice, David; Pass, Harvey; Asamura, Hisao; Waller, David; Edwards, John; Weder, Walter; Hoffmann, Hans; van Meerbeeck, Jan P
BACKGROUND:: The current staging system for malignant pleural mesothelioma (MPM) is controversial. To plan revisions of this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. Initial analyses focus on patients managed surgically. METHODS:: Participation was solicited from centers known to have MPM registries. Common data elements were analyzed by the International Association for the Study of Lung Cancer Staging Committee Statistical Center. Survival was analyzed by the Kaplan-Meier method, prognostic factors by log rank and Cox regression model. p Value less than 0.05 was significant. RESULTS:: Data included 3101 patients (15 centers, 4 continents). Demographics: median age 63 years, 79% men, 62.3% epithelioid tumor. Best tumor, node, metastasis (bTNM) stages were: I (11%), II, (21%), III (48%), and IV (20%). Curative-intent surgery was performed in 1494 patients (64.5%). Median survivals by clinical TNM and pathological TNM were similar: stage I, 21 months; stage II, 19 months; stage III, 16 months; and stage IV, 12 months. Median survival by histology: epithelioid 19 months, biphasic 13 months, and sarcomatoid 8 months. By multivariable analyses, significant differences in overall survival were seen for: T4 versus T3 and T3 versus T2 but not T2 versus T1; N0 versus N1 and N2 but not N1 versus N2; stages III and IV versus I but not II versus I; epithelioid histology versus other; age of female versus age of male; and palliative versus curative-intent surgery. CONCLUSIONS:: This is the largest international database examining outcomes in surgically managed MPM patients. Survival differences reported from smaller databases are confirmed but suggest the need to revise tumor and node staging.
PMID: 23070243
ISSN: 1556-0864
CID: 181212
Fibulin-3 as a blood and effusion biomarker for pleural mesothelioma
Pass, Harvey I; Levin, Stephen M; Harbut, Michael R; Melamed, Jonathan; Chiriboga, Luis; Donington, Jessica; Huflejt, Margaret; Carbone, Michele; Chia, David; Goodglick, Lee; Goodman, Gary E; Thornquist, Mark D; Liu, Geoffrey; de Perrot, Marc; Tsao, Ming-Sound; Goparaju, Chandra
BACKGROUND: New biomarkers are needed to detect pleural mesothelioma at an earlier stage and to individualize treatment strategies. We investigated whether fibulin-3 in plasma and pleural effusions could meet sensitivity and specificity criteria for a robust biomarker. METHODS: We measured fibulin-3 levels in plasma (from 92 patients with mesothelioma, 136 asbestos-exposed persons without cancer, 93 patients with effusions not due to mesothelioma, and 43 healthy controls), effusions (from 74 patients with mesothelioma, 39 with benign effusions, and 54 with malignant effusions not due to mesothelioma), or both. A blinded validation was subsequently performed. Tumor tissue was examined for fibulin-3 by immunohistochemical analysis, and levels of fibulin-3 in plasma and effusions were measured with an enzyme-linked immunosorbent assay. RESULTS: Plasma fibulin-3 levels did not vary according to age, sex, duration of asbestos exposure, or degree of radiographic changes and were significantly higher in patients with pleural mesothelioma (105+/-7 ng per milliliter in the Detroit cohort and 113+/-8 ng per milliliter in the New York cohort) than in asbestos-exposed persons without mesothelioma (14+/-1 ng per milliliter and 24+/-1 ng per milliliter, respectively; P<0.001). Effusion fibulin-3 levels were significantly higher in patients with pleural mesothelioma (694+/-37 ng per milliliter in the Detroit cohort and 636+/-92 ng per milliliter in the New York cohort) than in patients with effusions not due to mesothelioma (212+/-25 and 151+/-23 ng per milliliter, respectively; P<0.001). Fibulin-3 preferentially stained tumor cells in 26 of 26 samples. In an overall comparison of patients with and those without mesothelioma, the receiver-operating-characteristic curve for plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng of fibulin-3 per milliliter. In a comparison of patients with early-stage mesothelioma with asbestos-exposed persons, the sensitivity was 100% and the specificity was 94.1% at a cutoff value of 46.0 ng of fibulin-3 per milliliter. Blinded validation revealed an area under the curve of 0.87 for plasma specimens from 96 asbestos-exposed persons as compared with 48 patients with mesothelioma. CONCLUSIONS: Plasma fibulin-3 levels can distinguish healthy persons with exposure to asbestos from patients with mesothelioma. In conjunction with effusion fibulin-3 levels, plasma fibulin-3 levels can further differentiate mesothelioma effusions from other malignant and benign effusions. (Funded by the Early Detection Research Network, National Institutes of Health, and others.).
PMCID:3761217
PMID: 23050525
ISSN: 0028-4793
CID: 179282